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Prostate specific membrane antigen (PSMA) is overexpressed in prostatic adenocarcinoma (CaP), and its expression is negatively regulated by androgen stimulation. However, it is still unclear which factors are involved in this downregulation.  TMPRSS2-ERG  fusion is the most common known gene rearrangement in prostate carcinoma. Androgen stimulation can increase expression of the  TMPRSS2-ERG  fusion in fusion positive prostate cancer cells. The purpose of this investigation is to determine whether PSMA expression can be regulated by the  TMPRSS2-ERG  gene fusion. We employed two PSMA positive cell lines: VCaP cells, which harbor  TMPRSS2-ERG  fusion, and LNCaP cells, which lack the fusion. After 24 hours of androgen treatment, TMPRSS2-ERG mRNA level was increased in VCaP cells. PSMA mRNA level was dramatically decreased in VCaP cells, while it only has moderate change in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA expression both in the presence and absence of synthetic androgen R1881. Overexpressing  TMPRSS2-ERG  fusions in LNCaP cells downregulated PSMA both in the presence or absence of R1881, while overexpressing wild type ERG did not. Using PSMA-based luciferase reporter assays, we found  TMPRSS2-ERG  fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that downregulation of PSMA in androgen-treated VCaP cells appears partially mediated by  TMPRSS2-ERG  gene fusion.

Role of TMPRSS2-ERG Gene Fusion in Negative Regulation of PSMA Expression